Human alcoholics and FAS children often have an increased incidence of infectious diseases, which suggests that their immune functions are impaired. Abnormally elevated levels of glucocorticoids exert profound inhibitory effects on immune cell number and function, while abnormally decreased levels can induce inflammatory reactions. Our working hypothesis is that alcohol-induced activation of the hypothalamic-pituitary-adrenal (HPA axis alters the ability of this axis to respond to circulating interleukins with an appropriate secretion of glucocorticoid, corticotrophin-releasing factor (CRF), and/or ACTH, and that these pathological levels will compromise immune functions. The proposed work makes use of the novel finding in a rodent model that prior exposure to alcohol alters the ability of immune mediators such as interleukins to stimulate ACTH and glucocorticoid secretion. The purpose of this proposal is therefore to verify this finding under a variety of alcohol regimens,then extend it to address the question of the stage of development during which alcohol can influence the HPA axis' responsiveness to interleukins, and to investigate the mechanisms responsible for these changes. Exposure to an antigen represents a threat to homeostasis. In order to survive, mammalian organisms must make appropriate endocrine, metabolic and immune changes to this challenge. Essential to this response is the increased secretion of immune mediators produced by stimulated macrophages, which are called cytokines or interleukins. It is presently believed that one of the functions of these interleukins is to convey the occurrence of immune activation to the brain, and in particular to the hypothalamus where they stimulate the release of endogenous CRF and activate the hypothalamic- pituitary-adrenal (HPA) axis. While the release of interleukins is essential for orchestrating the early part of the immune response, equally important for the health of the organism is the presence of a mechanisms which, following completion of this initial phase, terminates interleukin release to prevent an "overshooting" reaction. Increased secretion of glucocorticoids, which is caused by the stimulatory effect of interleukins on the HPA axis, represents such a mechanism. Prior stimulation of the HPA axis, occurs following exposure to post- or prenatal alcohol, and can result in either the inhibition or the enhancement of the HPA axis' responsiveness to another stimulus. We presently do not know why such opposite effects can occur, but believe that hyper- or hyporesponsiveness of the HPA axis depends on the mode of alcohol exposure. Our hypothesis is that in rats treated with alcohol, the ability of the HPA axis to be activated by exogenously administered cytokines will be modified. Specific Aims #1 and 2 will investigate the pattern of cytokine-induced release of corticosterone, ACTH and/or CRF in rats exposed to alcohol post- or prenatally, respectively. The possible mechanisms mediating the effects of pre-or postnatal exposure to alcohol on HPA axis activity, such as alteration in pituitary responsiveness to CRF, in glucocorticoid feedback, and/or in CRF biosynthesis, will be investigated under Specific Aim #3.